Stem Cell Suicide Switch

Human embryonic stem cells swiftly kill themselves in response to DNA damage.

By | May 3, 2012

image: Stem Cell Suicide Switch An apoptotic mouse cellWikimedia Commons, Laboratory of Experimental Pathology, NIEHS

An apoptotic mouse cellWIKIMEDIA COMMONS, LABORATORY OF EXPERIMENTAL PATHOLOGY, NIEHS

Human embryonic stem cells give a whole new meaning to the phrase “taking one for the team.” Unlike any other known human cell type, hESCs are primed to immediately throw themselves on the sword if they experience any DNA damage, according to research published online today (May 3) in Molecular Cell.

Human embryonic stem cells (hESCs) form the early embryo and eventually give rise to every cell type in the body. Because of this, a rapid self-destruct mechanism activated by DNA damage may prevent potentially dangerous mutations from spreading through the developing organism, the authors concluded.

The data is “convincing,” wrote Christopher Navara, who studies stem cells at the University of Texas at San Antonio and was not involved in the research, in an email to The Scientist. “hES cells have adopted a number of unique cell cycle and cell death regulatory mechanisms” to balance their rapid proliferation with maintaining a stable, healthy genome, he wrote.

Four years ago, Mohanish Deshmukh and colleagues at the University of North Carolina at Chapel Hill found that neurons—which, unlike stem cells, do not divide—restrict apoptosis, or cell death, allowing them to survive through periods of stress or cell damage that might otherwise stimulate apoptosis. To explore apoptosis at the other end of the development spectrum, the researchers next analyzed human ESCs, which constantly divide.

They had two hypotheses: the hESCs would be highly resistant to apoptosis since there are only about 50 of them in the early embryo and thus each is valuable; or they would be highly sensitive to apoptosis since DNA damage in even a single cell would quickly spread through an embryo. “We figured it could go either way,” said Deshmukh. “We were very curious.”

First, the team doused hESCs in a chemotherapy drug that causes DNA damage. Almost 100 percent of the hESCs died in just 5 hours, compared to 24 hours for fibroblasts. The finding is “consistent with what we and others have observed regarding sensitivity to DNA damage in hES cells,” said Navara.

When Deshmukh’s team stressed the ESCs in other ways, such as damaging the cytoskeleton, the cells did not die as quickly, demonstrating their acute sensitivity to DNA damage. “DNA damage is the one insult these embryonic stem calls can’t tolerate,” said Deshmukh. “It’s catastrophic for them. Any mutations they occur will be propagated rapidly through the system.”

Apoptosis is traditionally a lengthy process that involves the activation of a protein called Bax, which travels to the mitochondria and initiates the release of caspases, or “executioner” proteins that cause cell death. To investigate how hESCs initiate the process so rapidly, the researchers tagged Bax with an antibody that lights up when the protein is active. They were surprised to find that Bax is already active in healthy hESCs, unlike every other cell type in which Bax is activated only when a cell is damaged or dying. “I was stunned,” said Deshmukh. “I thought something was wrong. We spent a lot of time convincing ourselves that these cells were healthy and not actively dying.”

The team also saw that active Bax was not located in the mitochondria but in the Golgi, a packaging organelle. It is possible that cells sequester active Bax there, like a gun locked in a case, to prevent it from accidentally triggering cell death. “The cells’ activated it and tethered it to a place where it is not causing immediate damage,” said Deshmukh. That way, Bax is ready to go at a moment’s notice.

Interestingly, as soon as hESCs began differentiating, even after just 24 hours, the cells no longer contained active Bax, suggesting that extreme sensitivity to DNA damage lasts only for a few days during early development.

The team is now investigating what makes Bax constitutively active in hESCs and how it is localized to the Golgi. Though hESCs are popular in regenerative medicine research, researchers still know little about their biology, said Deshmukh. “Most research focuses on how these cells become differentiated cells,” he said. “I’m amazed that we don’t understand much about their basic biology.”

R. Dumitru, et al. “Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis,” Mol Cell, doi:10.1016/j.molcel.2012.04.002, 2012.

 

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Comments

Avatar of: shelleyr12

shelleyr12

Posts: 3

May 9, 2012

The BAX that's located in the Golgi; is it a necessary component in the cell and if not, could it be extricated or subdued so as to not cause any harm?

Avatar of: shelleyr12

shelleyr12

Posts: 3

May 9, 2012

The BAX that's noted to be located in the Golgi; is it a "necessary" part of DNA or could it be destroyed before the possibility of it causing cell death?  What role does it play if any at all and could it be "removed" to cancel the possibilities of it causing any harm?

Avatar of:

Posts: 0

May 9, 2012

The BAX that's located in the Golgi; is it a necessary component in the cell and if not, could it be extricated or subdued so as to not cause any harm?

Avatar of:

Posts: 0

May 9, 2012

The BAX that's noted to be located in the Golgi; is it a "necessary" part of DNA or could it be destroyed before the possibility of it causing cell death?  What role does it play if any at all and could it be "removed" to cancel the possibilities of it causing any harm?

Avatar of:

Posts: 0

May 10, 2012

Bax isn't part of DNA, it's a protein.  It plays a very important role, it initiates apoptosis when the cell needs to coordinated its own death.  It shouldn't be thought of as causing harm.  If you got rid of it you would likely end up with something resembling cancer.

Avatar of: codyish

codyish

Posts: 1

May 10, 2012

Bax isn't part of DNA, it's a protein.  It plays a very important role, it initiates apoptosis when the cell needs to coordinated its own death.  It shouldn't be thought of as causing harm.  If you got rid of it you would likely end up with something resembling cancer.

Avatar of: alexandru

alexandru

Posts: 1457

May 11, 2012

I am glad that a Romanian scientist  explain scientifically what I have discovered theoretically
four years ago and sent to First
EMBO Conference on Centrosomes and Spindle Pole Bodies, 12-16
September 2008 Heidelberg, Germany, but not accepted.

My supposition was confirmed at the
conference by the researchers from University of Michigan - "Stem cell
centrosome misorientation"

There is a wireless communication
between Eve mtDNA cells and Adam mtDNA, existed only in xiphoid process, called
"one of man's ribs" (Genesis 2.21 and Paul, Hebrew 4.12).
 

Avatar of:

Posts: 0

May 11, 2012

I am glad that a Romanian scientist  explain scientifically what I have discovered theoretically
four years ago and sent to First
EMBO Conference on Centrosomes and Spindle Pole Bodies, 12-16
September 2008 Heidelberg, Germany, but not accepted.

My supposition was confirmed at the
conference by the researchers from University of Michigan - "Stem cell
centrosome misorientation"

There is a wireless communication
between Eve mtDNA cells and Adam mtDNA, existed only in xiphoid process, called
"one of man's ribs" (Genesis 2.21 and Paul, Hebrew 4.12).
 

Avatar of: shelleyr12

shelleyr12

Posts: 3

May 15, 2012

Thanks for clearing that up for me...I had found the article to be incredibly interesting. So the BAX is a protein living in a cell that helps the cell coordinate it's death if need be?

Avatar of:

Posts: 0

May 15, 2012

Thanks for clearing that up for me...I had found the article to be incredibly interesting. So the BAX is a protein living in a cell that helps the cell coordinate it's death if need be?

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